|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 24, No 15 (May 20), 2006: pp. 2225-2226 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.3785
Is There a Role for the Irreversible Epidermal Growth Factor Receptor Inhibitor EKB-569 in the Treatment of Cancer? A Mutation-Driven QuestionVall d'Hebron University Hospital, Barcelona, Spain In this issue of the Journal of Clinical Oncology, the results of the phase I study of EKB-569 in patients with solid tumors are presented.1 EKB-569 is a potent and irreversible inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase.2,3 In this study, EKB-569 was safe, exposure was dose proportional, and it had a prolonged mean terminal half-life, which allows for a daily administration schedule. The dose-limiting toxicity was grade 3 diarrhea, which is similar to other EGFR inhibitors. As with other anti-EGFR inhibitors, skin rash and asthenia were also observed. The maximum-tolerated dose was found to be 75 mg/d, both in the intermittent and in the continuous administration schedule, and a lower dose of 50 mg/d has been chosen for phase II studies because it is associated with fewer drug-related severe toxicities and there is a strong suggestion that this dose level results in biologically relevant concentrations in plasma and inhibits EGFR function in patients.4 On the basis of the results of this trial,1 EKB-569 clearly meets the early requirements for further clinical development; it is well tolerated, it has shown predictable pharmacokinetics, an optimal dose has been identified, it has the expected toxicities, and there is evidence of in vivo inhibition of the receptor. As usual with this class of agents, hints of clinical benefit were also observed. The critical question ahead for this and other anti-EGFR agents in early clinical development is whether they will be superior or complementary to the currently available anti-EGFR agents. The field of EGFR inhibitors is becoming increasingly crowded with the following two classes of agents: monoclonal antibodies against the extracellular domain of the receptor and low molecular weight tyrosine kinase inhibitors (for review, see Baselga and Arteaga5). These two classes of agents have partially different mechanisms of action and nonoverlapping clinical indications. Anti-EGFR monoclonal antibodies are approved in the treatment of colon cancer and may be soon approved in other indications such as head and neck tumors. In the class of low molecular weight EGFR tyrosine kinase inhibitors, gefitinib and erlotinib are approved for the treatment of non–small-cell lung cancer (NSCLC), and erlotinib recently obtained approval for the treatment of advanced pancreas carcinoma. Do we have any suggestion that EKB-569 may be superior or complementary to gefitinib and erlotinib? Superiority may be achieved by different means, such as broader or greater efficacy, enhanced safety, or a more convenient administration schedule. None of these means seem to apply to EKB-569. Although a potential advantage of an irreversible EGFR inhibitor would be an easier dosing schedule, both gefitinib and erlotinib are already administered on a convenient daily basis. In terms of additional disease-based indications, a phase II study of EKB-569 is underway in patients with advanced colorectal cancer (CRC). Although we need to wait for the outcome of this trial, one is tempted to speculate that EKB-569 will be inactive as a single agent in CRC based on the minimal activity of other EGFR tyrosine kinase inhibitors in CRC.6 It would also seem fair to wait for the results of currently ongoing studies of EKB-569 and chemotherapy in patients with pancreatic cancer and CRC. It seems more likely that the potential advantages of EKB-569 and other irreversible EGFR inhibitors in the treatment of cancer may be linked to the biology of EGFR itself. The EGFR is a transmembrane receptor tyrosine kinase of the ErbB family that is abnormally activated in many epithelial tumors. Ligand binding results in homo- or heterodimerization and activation of the highly conserved intracellular tyrosine kinase domain, resulting in phosphorylation of specific tyrosine residues that serve as docking sites of proteins whose recruitment activates a multitude of downstream signaling pathways, which, in turn, engage mitogenic signaling and other tumor-promoting activities. Clinical responses to gefitinib and erlotinib are highly dependent on the presence of EGFR somatic mutations that affect critical amino acids in the adenosine triphosphate–binding cleft of the tyrosine kinase domain of the receptor.7-9 Responses have also been reported in patients with EGFR gene amplification.10,11 EGFR mutations arise in the following four exons of the gene: substitutions for G719 in the nucleotide binding loop of exon 18, in-frame deletions within exon 19, in-frame insertions within exon 20, and substitution for L858 or L861 in the activation loop in exon 21. Interestingly, not all EGFR mutations result in enhanced sensitivity to gefitinib and erlotinib. Patients who initially respond to gefitinib or erlotinib may acquire secondary EGFR mutations that render them resistant to these agents, specifically the T790M mutation.12,13 T790M primary mutations may also occur in previously untreated patients.14 Primary transforming mutations may also be resistant to gefitinib and erlotinib; this has been recently shown by the identification of an exon 20 insertion mutant that is completely resistant to these inhibitors.15 In addition, the T790M mutation is present in some but not all patients with acquired resistance to gefitinib and erlotinib, indicating the presence of additional mechanisms of resistance such as increased receptor trafficking.16 The good news is that, in these patients with acquired or primary resistant mutations to gefitinib and erlotinib, the irreversible EGFR inhibitors EKB-569, HKI-272,17 CL-387,785,18 and CI-103319 have shown to be active at blocking receptor signaling and inhibiting growth at low concentrations.15,16,20 These findings imply that EKB-569 and other irreversible EGFR inhibitors should be studied in the treatment of NSCLC patients with acquired resistance to gefitinib or erlotinib and even upfront in the treatment of NSCLC patients with primary EGFR mutations resistant to gefitinib or erlotinib. However, at this time, we cannot rule out that irreversible inhibitors may be less active against gefitinib- or erlotinib-sensitive mutations. We seem to be moving towards EGFR mutation-specific therapy in NSCLC, an approach that is also being explored in BCR-ABL and KIT drug-resistant mutants.20 As the biology of EGFR mutations and acquired resistance to gefitinib and erlotinib is being elucidated, the burden is on us to develop these agents right in the clinic. We should aim at studying the clinical benefits of irreversible inhibitors in patients with preselected mutations and with acquired resistance to gefitinib and erlotinib, an approach that will require a careful patient selection process. The end result may be that a given EGFR inhibitor may not fit all mutations and that we may be entering an era of personalized mutation-based anti-EGFR therapy. Author's Disclosures of Potential Conflicts of Interest
The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES 1. Erlichman C, Hidalgo M, Boni JP, et al: Phase I study of EKB-569, an irreversible inhibitor of the epidermal growth factor receptor, in patients with advanced solid tumors. J Clin Oncol 24:2252-2260, 2006 2. Wissner A, Overbeek E, Reich MF, et al: Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles: The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor-2 (HER-2). J Med Chem 46:49-63, 2003[CrossRef][Medline] 3. Torrance CJ, Jackson PE, Montgomery E, et al: Combinatorial chemoprevention of intestinal neoplasia. Nat Med 6:1024-1028, 2000[CrossRef][Medline] 4. Casado E, Folprecht G, Paz-Ares L, et al: A phase I/IIA pharmacokinetic (PK) and serial skin and tumor pharmacodynamic (PD) study of the EGFR irreversible tyrosine kinase inhibitor EKB-569 in combination with 5-fluorouracil (5FU), leucovorin (LV) and irinotecan (CPT-11) (FOLFIRI regimen) in patients (pts) with advanced colorectal cancer (ACC). J Clin Oncol 22:255, 2004 (suppl; abstr 3543) 5. Baselga J, Arteaga CL: Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 23:2445-2459, 2005 6. Rothenberg ML, LaFleur B, Levy DE, et al: Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma. J Clin Oncol 23:9265-9274, 2005 7. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 8. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 9. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004 10. Bell DW, Lynch TJ, Haserlat SM, et al: Epidermal growth factor receptor mutations and gene amplification in non-small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 23:8081-8092, 2005 11. Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005 12. Kobayashi S, Boggon TJ, Dayaram T, et al: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786-792, 2005 13. Pao W, Miller VA, Politi KA, et al: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73, 2005[CrossRef][Medline] 14. Kosaka T, Yatabe Y, Endoh H, et al: Mutations of the epidermal growth factor receptor gene in lung cancer: Biological and clinical implications. Cancer Res 64:8919-8923, 2004 15. Greulich H, Chen T-H, Feng W, et al: Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants. PLoS Med 2:e313, 2005[CrossRef][Medline] 16. Kwak EL, Sordella R, Bell DW, et al: Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proc Natl Acad Sci U S A 102:7665-7670, 2005 17. Rabindran SK, Discafani CM, Rosfjord EC, et al: Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res 64:3958-3965, 2004 18. Discafani CM, Carroll ML, Floyd MB Jr, et al: Irreversible inhibition of epidermal growth factor receptor tyrosine kinase with in vivo activity by N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (CL-387,785). Biochem Pharmacol 57:917-925, 1999[CrossRef][Medline] 19. Smaill JB, Rewcastle GW, Loo JA, et al: Tyrosine kinase inhibitors: 17. Irreversible inhibitors of the epidermal growth factor receptor—4-(Phenylamino)quinazoline- and 4-(phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides bearing additional solubilizing functions. J Med Chem 43:1380-1397, 2000[CrossRef][Medline] 20. Carter TA, Wodicka LM, Shah NP, et al: Inhibition of drug-resistant mutants of ABL, KIT, and EGF receptor kinases. Proc Natl Acad Sci U S A 102:11011-11016, 2005
Related Article
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
$100,000 (N/R) Not Required
